Asthma is one of the most common diseases in industrialized countries, and in the United States accounts for about 1 of all health care costs. K. Weiss et al., New Engl. J. Med. 326, 862-866 (1992). There has been reported an alarming increase in both the prevalence and mortality of asthma over the past decade, Asthma-United States, 1980-1990, MMWR 41, 733-735 (1992), and occupational asthma is predicted to be the preeminent occupation al lung disease in the next decade. M. Chan-Yeung and J. Malo, European Resp. J. 7, 346-371 (1994) While the increasing mortality from asthma in industrialized countries might be attributable to the increased reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood. J. Gern and R. Lemanske, In Immunology and Allergy Clinics of North America 13, Bush, R. K. ed. W. B. Saunders Company, London, pp. 839-860 (1993).
Adenosine may constitute an important natural mediator of bronchial asthma. R. Pauwels et al., Clinical & Exp. Allergy 21 Suppl. 1, 48-55 (1991); S. Holgate et al., Annals of the New York Acad. Sci. 629, 227-236 (1991). The potential role of adenosine in human asthma is supported by the experimental finding that, in contrast to normal individuals, asthmatic individuals respond to aerosolized adenosine with marked bronchoconstriction. M. Church and S. Holgate, Trends Pharmacol. Sci. 7, 49-50 (1986); M. Cushley et al., Br. J. Clin. Pharmacol. 15, 161-165 (1983). Similarly, asthmatic rabbits produced using the dust mite allergic rabbit model of human asthma also were shown to respond to aerosolized adenosine with marked bronchoconstriction, while non asthmatic rabbits showed no response. S. Ali et al., Agents Actions 37, 165-176 (1992). Recent work using this model system has suggested that adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in asthma are mediated primarily through the stimulation of adenosine receptors. S. Ali et al., J. Pharmacol. Exp. Ther. 268, 1328-1334 (1994); S. Ali et al., Am. J. Physiol 266, L271-277 (1994).
Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist (see M. Cushley et al., Am. Rev. Resp. Dis. 129, 380-384 (1984)) and was found to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits (Ali, et al., supra). The pretreatment of allergic rabbits with another A1-specific receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), potently inhibited adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. Id. The therapeutic potential, however, of currently available adenosine Al receptor-specific antagonists is limited by their toxicity. H. Klitgaard et al., European J. Pharmacol. 242, 221-228 (1993). Theophylline has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. E. Powell et al., Pediatric Emergency Care 9, 129-133 (1993); S. Nasser and P. Rees, Drug Safety 8, 12-18 (1993); P. Epstein, Annals of Internal Med. 119, 1216-1217 (1993). The availability of an alternative strategy to downregulate adenosine-mediated bronchoconstriction would clearly be of therapeutic interest.